N-substituted benzhydrol, benzhydryl, and benzhydrylidene piperidine



2,898,339 lC p ted Aug. 1959 N-SUBSTITUTED BENZHYDROL, BENZHYDRYL, ANDBENZHYDRYLIDENE PIPERIDINE Keith W. Wheeler, Wyoming, and Jay K. Seylerand Frank P. Palopoli, Cincinnati, Ohio, and Frederick J. McCarty, AnnArbor, Mich., assignors to The Wm. S. Merrell Company No Drawing.Application July 29, 1957 Serial No. 674,601

'6 Claims. (Cl. 260-2934) Our invention relates to certain novelN-substituted benzhydrol, benzhydryl and benzhydrylidene piperidineswhich are useful as depressants for the central'nervous system. I

The novel compounds of our invention have the formula sjflt N t In theformula, S indicates that the ring is saturated. R is an acetyl,trifiuoroacetyl, chloroacetyl, carbethoxy, carboxypropionyl, ethoxalyl,carbamyl, ethylcarbamyl, ethylthiocarbamyl, dimethylsulfamyl orN-isonicotinoyl radical. A is a benzhydrol [-COH(C- H5)g],benzhydryl[CH(C H5) or a benzhydrylidene radical. In the benzhydrol and benzhydrylcompounds A is attached to a piperidine ring carbon atom at the 2 or 4position. In the benzhydrylidene compounds A is attached to a piperidinering'carbon atom in the 4 position.

The novel Z-and 4-benzhydrolpiperidines, which may also be termeddiphenyl-N-substituted piperidine carbinols, have the formula I LS e shThe novel 2- and 4-benzhydrylpiperidines have the formula s 11mm.

The novel. 4-benzhydrylidenepiperidines have the formula moan).

The compounds generally have utility for controlling nervous systemdisorders, including psychotic and psychoneurotic conditions, e.g.over-activity. All of the compounds exhibit'sedative or depressantactivity, without any hypnotic activity. Some of the compounds havedepressant activity with after eifects of stimulantactivity.

The compounds can be used in oral dosages within States Patent O therange of about 25 to about 1500 to 2000 mg. daily.

Parenterally, dosages within the range of about 25 to about 500 mg.daily can be used. Parenteral administrat'ion is preferably bythe'intramuscular route since most of the compounds are insoluble inwater.

The novel compounds are prepared by reactingbenzhydrol-, benzhydrylorbenzhydrylidenepiperidine vvith a compoundcontaining'the desired Rsubstituent. An acid acceptor such as triethylamine can be used toaccept free acids produced in the reaction.

The novel compounds will be further illustrated by the followingexamples.

EXAMPLE 1 Diphenyl-4-(N-acetyDpiperidine carbinol A solution of 14 g.(0.0525 mole) of diphenyl-4- piperidine carbinol(m,-diphenyl-4-piperidinemethanol asdescribed in Patent No. 2,804,422,filed December 29, 1956, of Schumann et a1.) and 5.3 g. (0.0525 mole)triethylamine in m1. chloroform was prepared. To

this solution was added dropwise, with stirring, 5.8 g.

(0.057 mole) acetic anhydride. The temperature was kept below 35 C. bytap water cooling. After the resulting clear solution had stood at roomtemperature overnight precipitation had occurred. The crystals werecollected, then the filtrate was heated at reflux for 1 hour, dilutedwith an equal volume of petroleum ether, and chilled. Another crop ofcrystals was obtained. The two crops were combined, then recrystallizedfrom chloroform and petroleum ether. Yield: 13.4 g. of

fine, white needles of-diphenyl-4-(N-acetyl)piperidine carbinol, ,M.P.197-8 C.

Analysis.--Calcd. for C H O N: C, 77.62; H, 7.49;

N, 4.53. Found:- C, 77.32; H, 7.43; N, 4.60.

This compound exhibits activity as .a depressant for the central nervoussystem.

'EXAMPLE 2 Diphnyl-4-(N-trifluoroacetyl)piperdine carbinol To a stirredsolutionof 13 g. (0.0488 mole) diphenyl- 4-piperidine carbinol and 5 g.(0.049 mole) triethylamine in '100 ml. dry" benzene was'added, dropwise,10.2 g. (0.0.488 mole) trifluoroacetic anhydride. 'The r' temperaturewas kept below 25 C. with tap water cool- EXAMPLE 3 VDiphenyl-Z-(N-trifluoroacetyl)piperidihe carbinol Following theprocedure given in Example 2, 10 g. (0.0375 mole) diphenyl-Z-piperidinecarbinol (a cediphenyl-Z-piperidinemethanol as' described in U.S. Patent2,624,739 to Werner et a1.) 4 g. (0.0395 mole) triethylamine and 8.4 g.(0.04 mole) trifluoroacetic anhydride in 100 ml. dry benzene gave 4.9 g.of product, diphenyl- 2-(N trifiuoroacetyl)piperidine carbinol, M.P. C.Analysis.-Ca1cd. for C H NO F C, 66.10; H, 5.55;.N, 3.85. Found: C,66.23; H, 5.65;.N, 4.10.

Thiscompound exhibits activity as a depressant for the central nervoussystem.

3 EXAMPLE 4 N-carbethoxy-a,a-diphenyl-4-piperidine carbinol Followingthe procedure given in Example 2, 17.5 g. (0.065 mole)diphenyl-4-piperidine carbinol, 8.7 g. (0.08 mole) ethyl chlorocarbonateand 8g. (0.08 mole) triethylamine in 100 ml. benzene gave 12 gm. ofproduct, N-carbethoxy-a,a-diphenyl 4 piperidine carbinol, M.P. 160-1 C.

Analy'sis.Calcd. for C H NO C, 74.35; H, 7.43. Found: C, 74.60; H, 7.42.

This compound exhibits activity as a depressant for the central nervoussystem.

EXAMPLE N-carbethoxy-m,a-diphenyl-2-piperidine carbinol Seven andone-half grams (0.069 mole) ethyl chlorocarbonate was added dropwise toa stirred solution of 37 g. (0.138 mole) diphenyl-Z-piperidine carbinolin 100 ml. dry benzene. 70 C. for 3 hours, then the solution cooled.After removal of the precipitated diphenyl-Z-piperidine carbinolhydrochloride, by filtration, the filtrate was concentrated. The residuewas then crystallized from petroleum ether. Yield: 13 g. ofN-carbethoxy-u,a-diphenyl-2-piperidine carbinol, M.P. 133-4 C.

Analysis.Ca.lcd. for C H NO C, 74.31; H, 7.42; N, 4.13. .Found: C,74.08; H, 7.10; N, 3.81.

This compound exhibits activity as a depressant for the central nervoussystem.

EXAMPLE 6 N-dimethylsulfamylu,oc-diphenyl-4piperidine carbinol Followingthe procedure given in Example 2, 20 g. (0.066 mole)diphenyl-4-diperidine carbinol. hydrochloride, 14 g. (0.138 mole)triethylamine and 9.6 g. (0.067 mole) dirnethylsulfamyl chloride in 300ml. dry toluene gave 5.5 g. of product, N-dimethylsulfamyl-a,a-diphenyl- 4-piperidine carbinol, M.P. 1724 C.

Analysis.Calcd. for C H N O S: C, 64.13; H, 7.00; N, 7.48. Found: C,64.52; H, 6.96; N, 7.14.

This compound exhibits activity as a depressant for the central nervoussystem.

EXAMPLE. 7 p a N-chloroacelyl-a,a-diphenyl-4-piperidine carbinol' Theprocedure given in Example 2 was followed, using '14 g. (0.0525 mole)diphenyl-4-piperidine carbinol, 5.3

g. (0.0525 mole) triethylamine and 6' g. (0.053 mole) chloroacetylchloride. Obtained 4.4 g. product,N-chloroacetyl-oc,a-diphenyl-4-piperidine carbinol, M.P. 154-- 5 C.

Analysis.Calcd. for C H NO Cl: C, 69.85; H, 6.45; N, 4.07. Found: C,69.97; H, 6.62; N, 4.09. i

This compound exhibits activity as a depressant for the central nervoussystem. i

EXAMPLE 8 N-(fi-carboxypropionyl) -qc,oz-diphenyl4-piperidine I carbinolFive and one-half grams (0.055 mole) of succinic an hydride wasdissolved in 100 ml. of 1,2-dim'ethoxyethane at slightly above roomtemperature, then 14.5 g. (0.054 mole) diphenyl-4-piperidine carbinolwas added insmall portions over a period of 10 minutes. The temperaturerose from 31.5 C. to 39 C. This mixture was kept at 60-65" C. for 30minutes, then allowed to stand at room temperature for 20 hours, thenchilled; The first crop of 3.7 g., M.P. 190200 C. was discarded. Thesecond crop, on concentration of the filtrate, amounted to 10.0 g. ofproduct, M.P. 155-8 C. Recrystalization from chloroform and petroleumether gave 8.3 g.'of product, N-(p-carboxypropionyl) -a,a-diphenyl 4piperidine car- The temperature was maintained at r 4 binol, isolated asthe monohydrate, M.P. 172.5-173" C. Neutral equivalent: calcd., 385.4;found, 384.6.

Analysis.-Calcd. for C H NO 'H O: C, 68.55; H, 7.06; N, 3.63. Found: C,68.31; H, 6.67; N, 3.70.

This compound exhibits activity as a depressant for the central nervoussystem.

This compound also forms salts, e.g. the sodium salt which is watersoluble.

EXAMPLE 9 N-carbamyl-a,a-diphenyl-4-piperidine carbinol Fifteen grams(0.05 mole) of diphenyl-4-piperidine carbinol hydrochloride wasdissolved in 600 ml. of water at 55 C. The solution was filtered and asolution of 6 g. (0.075 mole) of potassium cyanate in 30 ml. of waterwas added to the filtrate. An immediate precipitate appeared. Enoughacetone, about 200 ml., was added to dissolve the precipitate at 58 C.The solution was allowed to stand at room temperature for 5 hours, thenchilled at 0 overnight. Filtration gave 10.7 g. of lustrous whitecrystals, M.P. 198-200 C. An additional 2.7 g. of product (M.P. 198-200C.) was obtained by removing the acetone at the water pump. The combined13.4 g. was recrystallized from chloroform-petroleum ether to give 10.3g. of product, N-carbamyl-u,adiphenyl-4-piperidine carbinol, M.P.200.5201 C.

Analysis.-Calcd. fOI' CIQHZZNZOZ: C, H, N, 9.03. Found: C, 73.29; H,7.23; N, 9.42.

This compound exhibits activity as a depressant for the central nervoussystem.

y EXAMPLE l0 N-carliamyl-a,u-diphenyl-Z-piperidine carbinol Followingthe procedure given in Example 9, 18.2 g. (0.06 mole)diphenyl-Z-piperidine carbinol hydrochloride and 6 g. (0.074 mole) ofpotassium cyanate in 500 ml. of water gave, finally, 1.5 glof product,N-carbamyl-a,udiphenyl-2-piperidine carbinol, M.P. 170-1" C.

Analysis-Calm. for C H N O C, 73.50; H, 7.15; N, 9.03 Found: c, 73.73;H, 7.20; N, 9.21.

I This compound exhibits activity as a depressant for the centralnervous system.

EXAMPLE 11 Diphenyl-4-(N-ethylcarbamyl)piperidine carbinol Seventeen andeight-tenths grams (0.067 mole) diphenyl-4-piperidine carbinol wasdissolved in 300 ml. dry benzene at 45 C. Five grams (0.0715 mole) ethylis'ocyanate was then added portionwise. Some precipitation occured. Thesuspension was heated on the steam bath for 2 hours, then chilled inice. Collection of the precipitate (20.8 g., M.P. 21014 C.) followed byrecrystallization of 10 g. from ethanol-petroleum ether gave 8 g. ofproduct, diphenyl-4-(N-ethylcarbamyl)-piperdine carbinol, M.P. 213-14"C.

Analysis.-Calcd. for C H N O C, 74.52; H, 7.75; N, 8.28. Found: C,74.16; H, 7.81; N, 8.50.

This compound exhibits activity as a depressant for the central nervoussystem.

EXAMPLE l2 Diphenyl-Z-(N-ethylcarbamyl)piperidine carbinol Following theprocedure given in Example 11, 10 g- (0.0375 mole) diphenyl-Z-piperidinecarbinol and 2.8 g. (0.0395 mole) ethyl isocyanate in ml. dry benzenegave 9.2 g. of product, diphenyl-2-(N-ethylcarbamyl) piperidinecarbinol,M.P. 128-9 C.

Analysis.Calcd. for C H N O C, 74.52; H, 77 N,8.28. Found: C, 74.51; H,7.60; N, 8.18.

This' compound' exhibits activity as a dcpressant'for th central nervoussystem,

5 EXA PLE 13 Diphenyl-4-(N-ethylthiocarbamyl)piperidine carbinol EXAMPLE14 I Diphenyl-Z-(N-ethylthiocarbamyl) piperidine carbinol Following theprocedure of Example 11, 15 g. (0.0563 mole) diphenyl-Z-piperidinecarbinol and 6 g. (0.069 mole) ethyl isothiocyanate in 100 m1. toluenegave 4 g. of product, diphenyl-2-(N-ethylthiocarbamyl)piperidinecarbinol,M.P. 136-7 C.

Analysis.-Calcd. for C H N OS: C, 71.15; H, 7.40; N, 7.90. Found: C,70.96; H, 7.64; N, 7.88.

This compound exhibits activityas a depressant for the central nervoussystem.

EXAMPLE 15 Di phenyl-4 (N -isonic0tin0yl piperidzne carbinol Followingthe procedure of Example 1, 14 g. (0.05 mole) diphenyl-4-piperidinecarbinol, 5.3 g. (0.05 mole) triethyl amine, and 13 g. (0.057 mole)isonicotinic acid anhydride gave g. of product, diphenyl-4-(N-isonicotinoyl)piperidine carbinol, M.P. 2313 C.

Analysis.-Calcd. for C H N O C, 77.41; H, 6.50; N, 7.52. Found: C,76.96; H, 6.61; N, 7.61.

This compound exhibits activity as a depressant for the central nervoussystem.

EXAMPLE 16 N -acety l-4 -benzhydry lidenepiperidine4-benzhydrylidenepiperidine was prepared as follows. A suspension of 100g. (0.33 mole) of diphenyl-4-piperidine-carbinol hydrochloride in 700ml. of a 1:1 solution of concentrated sulfuric acid in Water was heatedon the steam bath, with stirring, for 7 hours. The resulting purplesolution was poured over ice and the precipitate which formed wascollected. Recrystallization of this material from water gave 95 g. ofthe sulfatesalt of 4- benzhydrylidenepiperidine, M.P. 246-7 C. This wassuspended in a mixture of 400 ml. of water containing 22 g. (0.55 mole)sodium hydroxide, and 600 ml. benzene, and the mixture heated on thesteam bath, with stirring, until all of the solid had gone intosolution. About 1 hour was required. The benzene layer was separated,washed with water, a saturated solution of sodium chloride in water, anddried over magnesium sulfate. Removal of the benzene and crystallizationof the residue from petroleum ether (B.P. 7090) gave 65.5 g. (80%) of4-benzhydrylidenepiperidine, M.P. 86-8 C.

Analysis-Called. C H N: percent C, 86.72; H, 7.68. Found: percent C,86.89; H, 7.68.

The hydrochloride melted at 28992.

Analysis.--Calcd. C H NHCl: percent C, 75.65; H, 7.06. Found: percent C,75.63; H, 7.07.

To a stirred solution of 12.5 g. (0.05 mole) 4-benzhydrylidenepiperidineand 5.05 g. (0.05 mole) triethylamine in 100 ml. dry benzene, 4 g. (0.05mole) acetyl chloride was added dropwise. The temperature was kept below25 C. with tap water cooling. After addition of the acetyl chloride themixture was heated to and maintained at 50 C. for 2 hours. The benzenesolution was cooled, then washed with water in a separatory funnel. Thebenzene layerwas separated, dried over MgSO and the henzene removed bydistillation. Crystallization of the residue from alcohol-petroleumether gave 86 gm. of. a

6 white product, N-acetyl 4 benzhydrylidenepiperidine, M.P. 114-15 C.

Analysis.-Ca1cd. for C H NO: C, 82.44; H, 7.26; N, 4.81. Found: C,82.20; H, 7.15; N, 4.90.

This compound exhibits activity as a depressant for the central nervoussystem.

EXAMPLE 17 4-benzhydryl-N-trifluoroacety lpiperidine Following theprocedurein Example 16, 10 g. (0.04 mole) 4-benzhydrylpiperidine (Suryand Hofiman, Helv. Chem. Acta, 37, 2133, 1954), 4.6 g. (0.045 mole)triethylamine and 9.4 g. (0.045 mole trifluoroacetic anhydride gave 8gm. of a white crystalline product,4-benzhydryl-N-trifluoroacetylpiperidine, M.P. 151-3 C.

Analysis. ---Calcd. for C H NO F C, 69.15; H, 5.80; N, 4.03. Found:C,-69.31; H, 6.15; N, 4.14.

This compound exhibits activity .as a depressant for the central nervoussystem.

EXAMPLE 18 4-benzhydrylidene-N-trifluoroacetylpiperidine Following theprocedure given in Example 16, 9.4 g. 0.045 mole) trifluoroaceticanhydride, 9.5 g. (0.04 mole) 4-benzhydrylidenepiperidine and 4.6 g.(0.045 mole) triethylamine in 100 ml. dry benzene gave 9.5 g. of aproduct, '4 benzhydrylidene-N-trifluoroacetylpiperidine, M.P. 8890' C;

Analysis.-Calcd. for C H NOF C, 69.55; H, 5.25;" N, 4.06. Found: C,70.04; H, 5.29; N, 4.30.

This compound exhibits activity as a depressant for the central nervoussystem.

EMMPLE 19 4-benzhydrylidene-N-carbethoxypipei'idine Following theprocedure given in Example 16, 12.5 g. (0.05 mole)4-benzhydrylidenepiperidine, 5.5 g. (0.055 mole) ethyl chlorocarbonateand 5.5 g. (0.055 mole) triethylamine in 100 ml. dry benzene gave 5.5 g.of a prod uct, 4 benzhydrylidene N carbethoxypiperidine, M.P. 120-2 C.

Analysis.Calcd. for C H O N: C, 78.49; H, 7.21; N, 4.36. Found: C,78.16; H, 7.10; N, 4.60.

This compound exhibits activity as' a depressant for the centralnervoussystem.

' EXAMPLE 20 4-benzhydryl-N-carbethoxypiperidine ethyl-chlorocarbonateand 4.5 g. (0.045 mole) triethyl amine in 75 m1. dry benzene gave 5.3 g.of a product, 4-

benzhydryl-N-carbethoxypiperidine, M.P. 724 C.

Analysis.-Calcd. for C H NO C, 78.00; H, 7.79; N, 4.33." Found: -C,77.65; 'H, 7.86; N, 4.32.

This compound exhibits activity as a depressantfor the central nervoussystem. followed .by, after a period of hours, activity as a stimulantfor the nervous system.

- EXAMPLE 21 j Z-benzhydryl-N-carbethoxypiperidine To a stirred solutionof 32 g. (0.127 mole) of 2-benzhydrylpiperidine (Sury'and Hoffman, Helv.Chem. Acta, 37, 2133, 1954) in 150ml. dry benzene, 6.8 g. (0.063 mole)ethyl chlorocarbonate was added dropwise.

Shortly after the end of addition of the chlorocarbonate precipitationoccurred. The. temperature of the solution .reached a maximum of 45 C.Stirringwascontinued for 3 hours, without'external heating. Theprecipitate was removed by filtration, then the benzene was removed fromthe filtrate at the water pump. Crystallization of :the residuefrompetroleum ether (B.;P.,70- C.) gave 17.5 g. of tan product, M.P. 102-5C. ;.Recrystal1ization from,v alcohol and'petroleurn. ether gave, ,8 g.of a central nervous system.

7 pgodct, 2-benzhydryl-N-carbethoxypiperidine, M.P. 115-Analysis.-Calcd. for C H NO C, 78.00; H, 7.79; N, 4.33. Found: C, 78.11;H, 7.64; N, 4.45.

This compound exhibits activity as a depressant for the central nervoussystem followed by, after a period of hours, activity as a stimulant forthe nervous system.

EXAMPLE 22 4-benzhydryl-N-dimethylsulfamylpiperidine Following theprocedure given in Example 16, g. (0.04 mole) 4-benzhydrylpiperidineand' 4.5 g. (0.045 mole) triethylarnine in 100 ml. dry benzene wasadded, dropwise, to a stirred solution of 6.4 g. (0.045 mole)dimethylsulfamyl chloride in 50 ml. benzene at 6070 C. By this means 85g. of a product, 4-benzhydryl-N-dimethylsulfarnylpiperidine wasobtained, M.P. 107-9 C.

Analysis.Calcd. for CZDHZGNZOZSZ C, H, N, 7.82. Found: C, 67.48; H,7.50; N, 7.44.

This compound exhibits activity as a depressant for the central nervoussystem.

EXAMPLE 23 4-benzhydrylidene-N-(,B-carboxylpropionyl) piperidine To asolution of 5.5 g. (0.055 mole) succinic anhydride in 100 ml. of1,2-dimethoxyethane was added, in portions and with stirring, 12.5 g.(0.05 mole) 4-benzhydrylidenepiperidine. The solution was maintained at60-70 C. for 1 hour, then at room temperature for 1 /2 hours. It wasfiltered and the filtrate was concentrated. The residue solidified. Itwas washed with hot distilled water and collected on a filter.Recrystallization from ethyl acetate-petroleum ether gave 6.5 g. of aproduct, 4-benzhydrylidene N (B carboxypropionyl)piperidine, M.P. 1423C.

Analysis.Calcd. for C H NO C, 75.64; H, 6.63; N, 4.01. Found: C, 75.79;H, 6.76; N, 4.26.

This compound also forms salts, e.g. the sodium salt which is watersoluble.

This compound exhibits activity as a depressant for the central nervoussystem.

EXAMPLE 24 4-benzhydryl-N-(,B-carboxypropionyl) piperidine Following theprocedure given in Example 23, 10 g; (0.04 mole) 4-benzhydrylpiperidineand 4.5 g. (0.045 mole) succinic anhydride in 75 ml. 1,2-dimethoxyethanegave 9 gm. of a product, 4-benzhydryl-N-(fl-carboxypropionyl)piperidine,M.P. 165--6 C. r p

Analysis.Calcd.-for C H NO C, 75.20; H, 7.17;

,N, 3.99. Found: C, 75.58; H, 7.51; N, 4.13.

This compound also forms salts, e.g. the sodium salt which is Watersoluble. This compound exhibits activity as a depressant for the EXAMPLE2s 4-benzhydrylidene-N-carbamylpiperidine To a solution of 12.5 g. (0.05mole) of 4-benzhydry1idenepiperidine in 400 ml. of water containing 6ml. concentrated hydrochloric acid, at 50 C. was added, over the 9period of a minute or two, a solution of 5 g. (0.062 mole)Analysis.Calcd. for C19HzoN2O: C, 78.03; H, 6.90;

'N, 9.58. Found: C, 78.27; H, 6.98; N, 9.30.

This compound exhibits activity as a depressant for the 8 centralnervous system followed by, after a period of hours, activity as astimulant for the nervous system.

EXAMPLE 26 4-benzhydryl-N-carbamylpiperidine Following the proceduregiven in Example 25, 12 g. (0.0476 mole) 4-benzhydrylpiperidine, 4.85 g.(0.06 mole) potassium cyanate and 6 ml. concentrated hydrochloric acidin 400 ml. of water gave 5.5 g. of product,4-benzhydryl-N-carbamylpiperidine, M.P. 16370 C.

Analysis.Calcd. for C H N O: C, 77.51; H, 7.53; N, 9.52. Found: C,77.61; H, 7.57; N, 8.83.

This compound exhibits activity as a depressant for the central nervoussystem.

EXAMPLE 27 Z-benzhydryl-N-carbamylpiperidine Following the proceduregiven in Example 25, 14.3 g. (0.05 mole) 2-benzhydry1piperidinehydrochloride and 6.5 g. (0.08 mole) potassium cyanate in 400 ml. ofwater gave 4 g. of product, 2-benzhydryl-N-carbamylpiperidine, M.P.163-4" C.

" Analysis.Calcd. for C H N O: C, 77.51; H, 7.53;

N, 9.52. Found: C, 77.36, H, 7.47; N, 9.11.

This compound exhibits activity as a depressant for the central nervoussystem.

EXAMPLE 28 4-benzhydrylidene-N-ethylcarbamylpiperidine 'N, 8.75. Found:C, 78.66; H, 7.44; N, 8.51.

This compound exhibits activity as a depressant for the central nervoussystem.

EXAMPLE 29 4-benzhydryl-N-ethylcarbamylpiperidine Following theprocedure of Example 28, 10 g. (0.04 mole) 4-benzhydrylpiperidine and3.2 g. (0.04 'mole) ethyl isocyanate in ml. benzene gave 6 g. ofproduct, 4-benzhydryl-N-ethylcarbamylpiperidine, M.P. 173-9 C.

Analysis.Calcd. for C H N O: C, 78.24; H, 8.13; N, 8.69. Found: C,78.65; H, 8.32; N, 8.58.

This compound exhibits activity as a depressant for the central nervoussystem.

EXAMPLE 30 4-benzhydrylia'ene-N-ethylthiocarbamylpiperidine Followingthe procedure given in Example 28, 10 g. (0.04 mole)4-benzhydrylidenepiperidine and 4 g. (0.045 mole) ethyl isothiocyanatein ml. dry benzene gave 10 gm. of product,4-benzhydrylidene-N-ethylthiocarbamylpiperidine, M.P. l679 C.

Analysis.-Calcd. for C H N S: C, 74.96; N, 8.33. Found: C, 75.40; H,7.27; N, 8.32.

This compound exhibits activity as a depressant for the central nervoussystem.

EXAMPLE 31 4-benzhydryl-N-ethylthiocarbamylpiperidine Following theprocedure given in Example 28, 10 g. (0.04 mole) 4-benzhydrylpiperidineand 4 g. (0.045 mole) ethyl isothiocyanate in 100 ml. dry benzene gave 8g. of

9 product, 4 benzhydryl N-ethylthiocarbamylpiperidine, M.P. 154-1555 C.

Analysis.Calcd. for C H N S: C, 74.51; H, 7.75; N, 8.28. Found: C,74.78; H, 7.77; N, 8.26.

This compound exhibits activity as a depressant for the central nervoussystem.

EXAMPLE 32 Z-benzhydryl-N-ethylthiocarbamylpiperidine EXAMPLE 33 4-benzhydrylidene-N-ethoxyalylpiperidine A solution of 12.5 g. (0.05 mole)4-benzhydrylidenepiperidine and 29.2 g. (0.2 mole) diethyl oxalate in100 ml. benzene was heated under reflux 3 hours, then petroleum etherwas added until a cloudiness appeared. The liquid was cooled andfiltered to give 16 g. of material, M.P. 1605 C. Recrystallization frombenzenepetroleum ether gave 8.3 g. of product,4-benzhydrylidene-N-ethoxalylpiperidine, M.P. 1689 C.

Analysis.Calcd. for C H NO C, 75.64; H, 6.63; N, 4.01. Found: C, 75.69;H, 6.66; N, 4.27.

This compound exhibits activity as adepressant for the central nervoussystem.

The following examples illustrate suitable pharmaceutical compositionscontaining the new compounds. In these examples, the quantities aregiven for single units, it being understood that in actual practice, thedosage forms will be prepared in suitable quantities, and the amounts ofthe materials used adjusted accordingly.

EXAMPLE 34 or rotary machine using a inch punch.

EXAMPLE 35 500 mg. tablets.-500 mg. of 4-benzhydrylN-carbethoxypiperidine (Example 20) in finely powdered form is admixedwith 60 mg. of corn starch and 100 mg. of powdered sugar and thengranulated with 10% gelatin solution. The granulation is dried andground to size suitable for tableting. About 1% magnesium stearate isadded as a lubricant, together with sufficient corn starch to give aweight of 700 mg. per tablet. The product is compressed on a singlepunch or rotary machine using a '95 punch.

The tablets of Examples 34 and 35 can be suitably coated if desired, as,for example, with sugar.

EXAMPLE 36 EXAMPLE 37 Capsule.-500 mg. of 4-benzhydrylN-carbethoxypiperidine (Example 20) is admixed with suificient cornstarch to give the proper bulk for the desired size capsule, and themixture is encapsulated.

EXAMPLE 38 lnjectable suspension, mg. per ml.--The following ingredientsare sterilized separately: 100 mg. of4-benzhydryl-N-carbethoxypiperidine (Example 20), 0.1 mg. of Tween 80and q.s. corn oil to make a final volume of 1 ml. These ingredients areadmixed aseptically. Particle size may be achieved by use of micronizedmaterial or by use of a ball mill, maintaining aseptic conditions. Theabove suspension may be administered subcutaneously and intramuscularly.

EXAMPLE 39 Oral suspension, 700 mg. per 15 ml.- mg. of Veegum H.V. ishydrated in about 9 ml. of water; 500 mg. of Tween 80, 700 mg. of4-benzhydryl N-carbethoxypiperidine (Example 20), color and flavor, asdesired, and water q.s. 15 ml. are added; the product is mixed well andhomogenized.

The other compounds of Examples 1 to 33 can be used in place of thecompound of Example 20 in the pharmaceutical preparations of Examples 34to 39.

We claim:

1. Compounds of the formulae selected from the group consisting of S I,a s)2.

( C 0H( a s)2 Q i R N CH(C6H 0 55):

Q i R and ( (Oaflr):

N I R wherein S indicates that the ring is saturated and R is selectedfrom the group consisting of acetyl, trifluoracetyl, chloroacetyl,carbethoxy, carboxypropionyl, ethoxalyl, carbamyl, ethylcarbamyl,ethylthiocarbamyl, dimethylsulfamyl and N-isonicotinoyl.

2. N dimethylsulfamyl ,0: diphenyl 4 piperidine carbinol.

3. Diphenyl 4 (N ethylthiocarbamyDpiperidine carbinol.

4. Diphenyl -.4 (N isonicotinoyDpiperidine carbinol.

5. 4 benzhydryl N carbethoxypiperidine. 6. 4 benzhydrylidene Ncarbamylpiperidine.

' No references cited,

1. COMPOUNDS OF THE FORMULAE SELECTED FROM THE GROUP CONSISTING OF 2.N - DIMETHYLSULFAMYL -A,A - DIPHENYL -4- PIPERIDINE CARBINOL.